Hard capsules

ABSTRACT

The present invention is directed to a hard capsule filled with a solution containing an active ingredient, wherein the shell of the capsule is made of a material containing a cellulose derivative, and the solution has a water content (w) of 10%&lt;w≦50%, and a water activity (a) of 0.60≦a≦0.90. The present invention provides a hard capsule which can hold an active-ingredient-containing solution of high water content, without impairing drug properties and stability, and sensation upon intake or eating sensation.

TECHNICAL FIELD

The present invention relates to hard capsules useful as medical drugs,quasi-drugs, cosmetics, and foods, and more particularly to stable hardcapsules filled with components of high water content.

BACKGROUND ART

In the medical and food appliance, capsules have conventionally beenemployed as suitable for improving the compliance upon use. Inparticular, hard capsules can be produced easily and therefore have beenwidely used for containing solid substances such as powder, granules,and fine granules, or oily substances.

Hard capsules typically contain gelatin as a shell-forming material, andtherefore, they have high solubility in water. When an active componentof high water content is directly charged in such a hard capsule, theinternal solution renders the gelatin shells dissolved or moistened,permitting deformation of the shape of the capsules or leakage of theinternal solution. As a result, the capsule has no value as a marketableproduct. Therefore, when the material to be encapsulated contains anaqueous solution, conventional approaches to avoiding the effect of thewater include addition of an excipient and solidification through, forexample, concentration or drying, performed before encapsulation. In thecase where a material is desired to be charged in capsules with itsliquidity being maintained, the material is suspended or emulsified inan oily substance before being encapsulated. Alternatively, glycerol isadded to the material and the resultant mixture is heated to evaporatethe water so as to attain a water content of 10% or less, followed byfilling in capsules formed of a cellulose derivative (U.S. Pat. No.6,238,696).

However, when subjected to a solidification process with heat, an animalor plant extract, such as a medicinal herb extract, is prone to changeits intrinsic taste, odor, properties, and components. Moreover, whenhard capsules containing such an extract are produced by a means ofsolidification through addition of an excipient, formation of suspensionor emulsification in an oily base, or reduction of a water content to10% or less (which is attained by adding glycerol in an amount as highas 20% to 80% on a final product basis, followed by heating), drawbackssuch as limitation being imposed on the amount of the active ingredientincorporated and a rise in production cost are unavoidable.

Meanwhile, soft capsules have been known to be able to contain liquidingredients. In the case of soft capsules, encapsulation of ingredientsof high water content, such as medicinal herb extracts, requires certaintechniques. For example, a moisture-containing plant extract and itsequivalent similar substance need to be emulsified with a fatty acidglyceride to thereby form soft capsules (Japanese Patent ApplicationLaid-Open (kokai) No. 52-35178), or, in order to impart water resistanceto a gelatin shell, a layered structure of gelatin sheets andpolysaccharide sheets need to be employed in producing soft capsules(Japanese Patent Application Laid-Open (kokai) No. 63-164858). Thesemeasures make production steps and production conditions intricate,raising a concern of increased cost.

Therefore, there has been a need for a technique capable of, throughsimple production steps and at low cost, encapsulating an aqueousextract of medicinal herbs, an aqueous extract of animal or plantorigin, or a similar substance without permitting volatilization ordegradation of active ingredients, while the resultant capsule productsdo not impair sensation (taste, odor, etc.) upon intake.

An object of the present invention is to provide hard capsules capableof stably enclosing a solution containing an active ingredient of highwater content, such as an aqueous extract of medicinal herbs, an aqueousextract of animal or plant origin, or a similar substance, withoutimpairing its quality for a prolonged period of time.

DISCLOSURE OF THE INVENTION

In view of the foregoing, the present inventors have performed extensivestudies on the relation between properties of the capsule shell andwater content of the solution to be encapsulated, and have found that ahigh-water-content solution can be successfully encapsulated in hardcapsules if a specific capsule shell is employed and the water contentand the water activity of the solution to be encapsulated can beproperly adjusted. The present invention has been achieved on the basisof this finding.

Accordingly, the present invention provides a hard capsule filled with asolution containing an active ingredient, wherein the shell of thecapsule is made of a material containing a cellulose derivative, themoisture content (w) of the solution to be encapsulated is 10%<w≦50%,and the water activity (a) is 0.60≦a≦0.90.

BEST MODE FOR CARRYING OUT THE INVENTION

The solution to be enclosed in the hard capsule of the present invention(hereinafter referred to as “internal solution”) is a solutioncontaining an active ingredient, and has a water content (w) of10%<w≦50% and a water activity (a) of 0.60≦a≦0.90.

As used herein, the term “water activity (a)” of a water-containingmedium is defined as the ratio P/P₀ of water vapor pressure of themedium (P) to vapor pressure of pure water (P₀) under the conditionswhere both pressures are measured at the same temperature. The wateractivity is a parameter representing activity of water in a medium.

The internal solution is not limited to aqueous solutions of activeingredients, but encompasses suspensions and O/W-type emulsions, as inthe case where a portion of active ingredients is difficult to dissolvein water. No particular limitation is imposed on the active ingredients,and they may be compounds or compositions of arbitrary substances, suchas medical drugs, natural materials, foods, herbal medicines in the formof extracts, plant extracts, and fermented matter.

Examples of the internal solution include aqueous extracts prepared bysubjecting medicinal herbs, animal- or plant-originating substances, orfermented matter to extraction with water or hydrated alcohol. Specificexamples falling under this category include herbal medicines in theform of aqueous extracts, such as ginseng, garlic, Acanthopanaxsenticosus Harms, Angelica sinensis, Rehmammia glutionosa, Citrusreticulate, Cuscuta chinensis, Schizandra chinesis, and Ophioposenjaponicus; aqueous extracts of herbal mixtures employed in kanpo(traditional Chinese medicine), available under the names of kakkon-to,bakumonto-to, sho-seiryu-to, orengedoku-to, shimotsu-to, andshakuyaku-kanzo-to; aqueous extracts of animal- or plant-origin,prepared from, for example, blue berries, green tea leaves, herbs,mushrooms, and mamushi (Japanese copperhead); and aqueous extracts offermented matter produced by fermenting grains, plants, or marineproducts with microorganisms such as koji mold, beni-koji mold, lacticacid bacterial acetic acid bacteria, Bacillus natto, and yeast. Otherexamples of the internal solution include solutions in water of aqueousvitamins such as vitamin B1, vitamin B2, niacin, vitamin B6, vitaminB12, vitamin C, pantothenic acid, biotin, folic acid, and pantothenylalcohol; solutions in water of dextromethorphan hydrobromide,acetaminophen, chlorphenylamine maleate, potassium guaiacolsulfonate,caffeine, dihydrocodeine phosphate, methylephedrine hydrochloride, andwater-soluble azulene; and suspensions of aldioxa, magnesium hydroxide,sucralfate, magnesium aluminometasilicate, and synthetic hydrotalcite.In particular, herbal medicines in the form of aqueous extracts andaqueous extracts of animal- or plant-origin are preferred, because theyare stable as aqueous solutions, and they can be handled in theirsolution form during the capsule formulation process.

If desired, the above-described internal solution may contain otheringredients, such as a sweetener, an acidulant, a stabilizer, athickener, a pH regulator, a preservative, a colorant, and a flavoringagent, which are generally used in the production of foods and drugs.

Here, examples of the sweetening agent include sugars such as sucrose,lactose, fructose, and glucose; sugar alcohols such as sorbitol,erythritol, mannitol, xylitol, and trehalose; glycyrrhizin; aspartame;and stevia. These may be used singly or in combination of two or morespecies.

As the acidulant, those commonly employed in the production of drugs andfoods may be used. Examples of acidulants include citric acid, malicacid, succinic acid, fumaric acid, tartaric acid, and lactic acid. Thesemay be used singly or in combination of two or more species.

Examples of the stabilizer include antioxidants such as ascorbic acid,erythorbic acid, and sodium pyrosulfite; dispersants such as sodiumpyrophosphate, sodium polyphosphate, and sodium metaphosphate;surfactants such as sucrose fatty acid esters, polyoxyethylenehydrogenated castor oil, and polyoxyethylene polyoxypropylene glycol;cyclodextrins such as cyclodextrin, glucosyl-cyclodextrin,maltosyl-cyclodextrin, and hydroxypropyl-cyclodextrin. These may be usedsingly or in combination of two or more species.

Examples of the thickener include polymers such as dextrin, sodiumalginate, propylene glycol alginate, tragacanth powder, xanthan gum,carrageenan, agar, pectin, carboxymethylcellulose-Na, hydroxypropylcellolose, polyvinyl alcohol, and polyvinyl pyrrolidone. These may beused singly or in combination of two or more species.

As for the pH regulator, those generally employed in the shape-impartingart may be used. Examples thereof include organic and inorganic acidssuch as hydrochloric acid, acetic acid, phosphoric acid, citric acid,malic acid, succinic acid, fumaric acid, tartaric acid, lactic acid, andsalts of any of these acids, alkalis such as sodium hydroxide, potassiumhydroxide, sodium hydrogencarbonate, and sodium dihydrogenphosphate.These may be used singly or in combination of two or more species.

Examples of preservatives include benzoic acids, sorbic acids,p-hydroxybenzoic esters, and salicylic acids. These may be used singlyor in combination of two or more species.

Examples of the colorant include caramel, sodium copper chlorophyllin,riboflavin sodium phosphate, indigocarmine, Brilliant Blue, tartrazine,sunset yellow, new coccine, amaranth, and erythrosine. These may be usedsingly or in combination of two or more species.

As for the flavoring agents, those generally employed for themanufacture of drugs and foods may be used, including, for example,fennel oil, orange oil, cinnamon oil, orange peel oil, mentha oil,vanillin, and eucalyptus oil. In addition to these, there may beemployed natural-originating flavors and compounded flavors which areproduced using any of these materials as raw material.

The foregoing internal solutions may be adjusted so as to be 10<w≦50% inthe water content (w) and 0.60≦a≦0.90 in the water activity (a),respectively. Preferably, the water content is 15≦w≦40% and the wateractivity is 0.60≦a≦0.85.

When the water content of the internal solution exceeds 50% or the wateractivity exceeds 0.90, water is present in an amount sufficient todissolve capsule shells, and therefore, these ranges should be avoided.Meanwhile, a water content less than 10% or a water activity below 0.60should also be avoided, because under such conditions, the viscosity ofthe internal solution extremely increases and prevents smooth flow ofthe solution, so that it becomes difficult to fill the shells duringproduction of capsules.

No particular limitation is imposed on the methods of adjusting watercontent (w) or water activity (a). For example, either of thefollowing 1) or 2) may be performed: 1) Soluble solid matter is causedto dissolve in cold water or lukewarm water until a target water contentand a target water activity are achieved, 2) in the case where ananimal- or plant-derived crude drug in the aqueous extract form isemployed, the relevant animal or plant material is extracted with wateror a water-ethanol mixture, and the resultant filtrate is concentratedwith the application of heat (25 to 50° C.) under reduced pressure untila target water content and a target water activity are achieved.

The capsule shells of the hard capsules according to the presentinvention are made of a material containing a cellulose derivative.

Examples of the cellulose derivative include hydroxypropylmethylcellulose, methylcellulose, hydroxypropyl cellulose, hydroxyethylcellulose, hydroxypropyl methylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carmelose, carboxymethylethylcellulose, cellulose acetate phthalate, and ethylcellulose. Inparticular, hydroxypropyl methylcellulose and methylcellulose arepreferred. The cellulose derivative may be used singly or in combinationof two or more species.

The cellulose derivative is incorporated in an amount of 15 to 30% byweight on the basis of the aqueous shell solution employed during theproduction of capsule shells. Also, like the case of the internalsolution, additives which are generally employed in the shape-impartingart, such as a gelling agent, a gelling aid, a colorant, a plasticizer,an emulsifier, a dispersant, and a preservative may be added.

Examples of the gelling agent include carrageenan, xanthan gum, locustbean gum, gellan gum, gum arabic, guar gum, tamarind-seed-derivedpolysaccharides, pectin, curdlan, gelatin, furcellaran, and agar.Preferably, carrageenan is employed. These materials may be used singlyor in combination of two or more species. The amount of the gellingagent to be added is 0.1 to 1.0% by weight on the basis of the aqueousshell solution employed for the production of capsule shells.

Examples of the gelling aid include water-soluble compounds whichrelease calcium ions, potassium ions, ammonium ions, sodium ions, ormagnesium ions, and specific examples include calcium chloride,potassium chloride, ammonium chloride, ammonium acetate, potassiumphosphate, potassium citrate, sodium chloride, magnesium sulfate, andorganic acids and water soluble salts thereof (for example, citric acidor sodium citrate). Water-soluble compounds providing potassium ions orammonium ions are preferably employed. The amount of the gelling aid tobe added is 0.01 to 1.0% by weight on the basis of the aqueous shellsolution employed for the production of capsule shells.

When a colorant is incorporated, any of ordinarily available additivesin the production of capsule shells may be used in suitable amounts.Examples of the colorant include caramel, sodium copper chlorophyllin,riboflavin sodium phosphate, indigocarmine, Brilliant Blue, tartrazine,sunset yellow, new coccine, amaranth, erythrosine, titanium oxides, andiron oxides. These may be used singly or in combination of two or morespecies.

Examples of the plasticizer include triethyl citrate, triacetin,glycerol, D-sorbitol, polyethylene glycol, acetylated monoglyceride, andsurfactants, and these may be used singly or in combination of two ormore species.

Moreover, if necessary, the hard capsules of the present invention maybe coated with a coating base, or two or more coating bases incombination, containing, for example, hydroxypropyl methylcellulosephthalate, hydroxypropyl methylcellulose acetate succinate,carboxymethylethyl cellulose, cellulose acetate phthalate,polyvinylacetal diethylaminoacetate, or a methacrylate copolymer.

The hard capsules according to the present invention can be produced asfollows. As described above, the water content (w) and the wateractivity (a) of an internal solution are adjusted to 10<w≦50% and0.60≦a≦0.90, respectively, and the resultant solution is filled into theaforementioned capsules by use of a conventional capsule filling machinedesigned to fill oily substances. Thereafter, in each capsule, the jointportion of the capsule body and its corresponding cap is sealed with anaqueous ethanol solution of a cellulose derivative, followed by dryingwith air.

Packaging of the thus-produced capsules may be performed in anyconventional mode, by the use of, for example, bottles, aluminum foil,PTPs, etc.

Preferred examples of the hard capsule of the present invention includethose having the property that the internal solution is a medicinal herbextract having a water content (w) of 33%≦w≦38% and a water activity (a)of 0.79≦a≦0.82; and the capsule shell contains hydroxypropylmethylcellulose, a gelling agent, and a gelling aid. In particular, acapsule which is #1 to #00 in its capsule size and packed in bottles oraluminum pouches is preferred.

EXAMPLES

The present invention will next be described in more detail by way ofexamples, which should not be construed as limiting the inventionthereto.

Example 1

A ginseng extract which had been concentrated under reduced pressurewith application of heat at 30° C. so as to have a water content fallingwithin a range of 32 to 48% and a water activity falling within a rangeof 0.80 to 0.89 was filled in #0 capsules made of hydroxypropylmethylcellulose, and in each capsule the joining portion of the capsulereceptacle and its corresponding cap was sealed with an aqueous ethanolsolution of hydroxypropyl methylcellulose, followed by drying with air.The resultant capsule samples were filled in glass bottles, and storedat 40° C. for 4 weeks. Whether there had been any leakage of theinternal solution from the capsules was checked by visual observation.The results are shown in Table 1. As a result, no liquid leakage wasvisually observed in respect of samples corresponding to a water contentof 39% or less and a water activity of 0.86 or less during the 4 weeks'storage. TABLE 1 Water content (%) 32 39 48 Water activity 0.80 0.860.89 1 week ∘ ∘ ∘ 2 weeks ∘ ∘ x 3 weeks ∘ ∘ x 4 weeks ∘ ∘ x∘: No leakage of waterx: Leakage of water

Example 2

In a manner similar to that described in Example 1, a garlic extractwhose water content and water activity had been adjusted to fall withinthe ranges of 32 to 49% and 0.73 to 0.87, respectively, was filled in #0capsules made of hydroxypropyl methylcellulose, followed by sealing anddrying with air, as in Example 1. The resultant capsule samples werefilled in glass bottles, and stored at 40° C. for 4 weeks. A visualobservation was performed to determine whether or not the internalsolution leaks from each capsule. As shown in Table 2, no liquid leakagewas visually observed in respect of samples corresponding to a watercontent of 41% or less and a water activity of 0.83 or less during the 4weeks' storage. TABLE 2 Water content (%) 32 41 49 Water activity 0.730.83 0.87 1 week ∘ ∘ ∘ 2 weeks ∘ ∘ x 3 weeks ∘ ∘ x 4 weeks ∘ ∘ x∘: No leakage of waterx: Leakage of water

Example 3

In a manner similar to that described in Example 1, a kakkon-to (whichis a decoction of roots of kudzu or Pueraria lobata Ohwi) extract whosewater content and water activity had been adjusted to fall within theranges of 33 to 47% and 0.79 to 0.87, respectively, was filled in #0capsules made from hydroxypropyl methylcellulose, followed by sealingand drying with air, as in Example 1. The resultant capsule samples werefilled in glass bottles, and stored at 40° C. for 4 weeks. A visualobservation was performed to determine whether or not the internalsolution leaks from each capsule. As shown in Table 3, no liquid leakagewas visually observed in respect of samples corresponding to a watercontent of 38% or less and a water activity of 0.82 or less during the 4weeks' storage. TABLE 3 Water content (%) 33 38 47 Water activity 0.790.82 0.87 1 week ∘ ∘ x 2 weeks ∘ ∘ x 3 weeks ∘ ∘ x 4 weeks ∘ ∘ x∘: No leakage of waterx: Leakage of water

Example 4

A fructose-glucose syrup whose water content and water activity had beenadjusted to 26% and 0.73, respectively, was filled in #0 capsules madefrom hydroxypropyl methylcellulose, followed by sealing and drying withair, as in Example 1. The resultant capsule samples were filled in glassbottles, and stored at 40° C. for 4 weeks. A visual observation wasperformed to determine whether or not the internal solution leaks fromeach capsule. As shown in Table 4, the samples showed no liquid leakageduring the 4 weeks' storage. TABLE 4 Water content (%) 26 26 Wateractivity 0.73 0.73 PH 3.0 4.6 1 week ∘ ∘ 2 weeks ∘ ∘ 3 weeks ∘ ∘ 4 weeks∘ ∘∘: No leakage of waterx: Leakage of water

Example 5

In a manner similar to that described in Example 1, a garlic extractwhose water content and water activity had been adjusted to fall withinthe ranges of 32 to 60% and 0.73 to 0.91, respectively, was filled inpreviously prepared methylcellulose capsules. Each capsule was sealed atits upper portion with an aqueous ethanol solution of methylcellulose,followed by drying with air. The resultant capsule samples were filledin glass bottles, and stored at 40° C. for 4 weeks. A visual observationwas performed to determine whether or not the internal solution leaksfrom each capsule. As shown in Table 5, no liquid leakage was visuallyobserved in respect of samples corresponding to a water content of 50%or less and a water activity of 0.87 or less during the 4 weeks'storage. On the other hand, samples of 60% water content showed waterdroplets on capsule surfaces, but its shape remained intact. TABLE 5Water content (%) 32 40 50 60 Water activity 0.73 0.82 0.87 0.91 1 week∘ ∘ ∘ x 2 weeks ∘ ∘ ∘ x 3 weeks ∘ ∘ ∘ x 4 weeks ∘ ∘ ∘ x∘: No leakage of waterx: Leakage of water

Comparative Example 1

A ginseng extract which had been concentrated under reduced pressurewith application of heat at 30° C. so as to have a water content fallingwithin a range of 32 to 48% and a water activity falling within a rangeof 0.80 to 0.89 was filled in #0 capsules made from gelatin, and in eachcapsule the joining portion of the capsule receptacle and itscorresponding cap was sealed with an aqueous solution of gelatin,followed by drying with air. The resultant capsule samples were filledin glass bottles, and stored at 40° C. for 4 weeks. Whether there hadbeen any leakage of the internal solution from each capsule was checkedby visual observation. The results are shown in Table 6. After one weekof storage, the liquid began to leak from each of the samples as shownin this table. TABLE 6 Water content (%) 32 39 48 Water activity 0.800.86 0.89 1 week x x x 2 weeks x x x 3 weeks x x x 4 weeks x x x∘: No leakage of waterx: Leakage of water

Comparative Example 2

In a manner similar to that described in Comparative Example 1, a garlicextract whose water content and water activity had been adjusted to fallwithin the ranges of 32 to 49% and 0.73 to 0.87, respectively, wasfilled in #0 capsules made from gelatin, followed by sealing and dryingwith air, as in Comparative Example 1. The resultant capsule sampleswere filled in glass bottles, and stored at 40° C. for 4 weeks. A visualobservation was performed to determine whether or not the internalsolution leaks from each capsule. The results are shown in Table 7.After one week of storage, the liquid began to leak from each of thesamples as shown in this table. TABLE 7 Water content (%) 32 41 49 Wateractivity 0.73 0.83 0.87 1 week x x x 2 weeks x x x 3 weeks x x x 4 weeksx x x∘: No leakage of waterx: Leakage of water

Comparative Example 3

In a manner similar to that described in Comparative Example 1, akakkon-to (which is a decoction of roots of kudzu or Pueraria lobataOhwi) extract whose water content and water activity had been adjustedto fall within the ranges of 33 to 47% and 0.79 to 0.87, respectively,was filled in #0 capsules made from gelatin, followed by sealing anddrying with air, as in Comparative Example 1. The resultant capsulesamples were filled in glass bottles, and stored at 40° C. for 4 weeks.A visual observation was performed to determine whether or not theinternal solution leaks from each capsule. The results are shown inTable 8. After one week of storage, the liquid began to leak from eachof the samples as shown in this table. TABLE 8 Water content (%) 33 3847 Water activity 0.79 0.82 0.87 1 week x x x 2 weeks x x x 3 weeks x xx 4 weeks x x x∘: No leakage of waterx: Leakage of water

Comparative Example 4

A fructose glucose syrup whose water content and water activity had beenadjusted to 26% and 0.73, respectively, was filled in #0 capsules madefrom gelatin, followed by sealing and drying with air, as in ComparativeExample 1. The resultant capsule samples were filled in glass bottles,and stored at 40° C. for 4 weeks. A visual observation was performed todetermine whether or not the internal solution leaks from each capsule.The results are shown in Table 9. After one week of storage, the liquidbegan to leak from each of the samples as shown in this table. TABLE 9water content (%) 26 26 water activity 0.73 0.73 PH 3.0 4.6 1 week x x 2weeks x x 3 weeks x x 4 weeks x x∘: No leakage of waterx: Leakage of water

INDUSTRIAL APPLICABILITY

The present invention provides hard capsules containing hold a solutionof an active ingredient with a high water content, without impairing theproperties and stability a drug or worsening the dosage characteristicsor texture. The hard capsules of the present invention can beefficiently produced, in that the liquid nature of their contentsenables the capsules to be filled with ease and the volume of thecontents are easily adjusted.

1. A hard capsule filled with a solution containing an activeingredient, wherein the shell of the capsule is made of a materialcontaining a cellulose derivative, and the solution has a water content(w) of 10%<w≦50%, and a water activity (a) of 0.60≦a≦0.90.
 2. The hardcapsule as described in claim 1, wherein the cellulose derivative is oneor more compounds selected from the group consisting of hydroxypropylmethylcellulose, methylcellulose, hydroxypropyl cellulose, andhydroxyethyl cellulose.
 3. The hard capsule as described in claim 1 or2, wherein the solution is an aqueous extract of a medicinal herb, ananimal- or plant-originating substance, or fermented matter.